The candidate, Dr. Calvin B. Williams, is a fellow in Pediatric Rheumatology at Washington University, St. Louis, with significant clinical and basic science experience, who seeks additional training in cellular immunology. For this, the outstanding research laboratory of Dr. Paul Allen was selected. Since joining the lab in July, 1994, Dr. Williams has been working on a project with the long-term objective of elucidating the mechanisms by which T cell tolerance develops to developmentally regulated and tissue specific MHC class II restricted self-antigens. The specific aims of this proposal are: (1) develop an inducible transgenic mouse system to control expression of the endogenous self protein hemoglobin(Hb); (2) determine the extent and types of tolerance which develop when expression of this self-antigen is limited to discrete developmental periods and to specific tissues. Substantial progress has been made resulting in two lines of transgenic mice. One of these expresses a tetracycline suppressible transactivator, and the other a chimeric protein containing the Hb (64-76) epitope contained within hen egg lysozyme. This system is designed to provide controlled expression of the Hb self antigen. These mice will be bred to T cell receptor transgenic-mice specific for Hb(64-76). Expression of the self-antigen will then be limited to discrete developmental periods and to specific tissues. The extent of tolerance will be determined by lymph node proliferation assay and FACS analysis of thymocytes and peripheral lymphocytes. Ultimately, Dr. Williams wishes to join the faculty at Washington University, where he will apply these studies towards understanding the failure of tolerance in human autoimmune disease, specifically in the pediatric population. The funds provided by this award are instrumental in allowing Dr. Williams to achieve these goals.